A central mental health issue is to better understand how cytokines produced in the brain during infection, trauma, and aging-related diseases, impact cognitive processes. Generally, the underlying molecular and cellular changes that lead to cognitive impairment by either acute or chronic cytokine exposure are largely unexplored. Current literature provides evidence that (i) behavioral performance can be impaired by administration of an immune challenge or a single cytokine, and that (ii) cytokine treatment impacts neural function and plasticity at the molecular/cellular level. However, there is a significant gap in information linking cytokine-mediated changes at the molecular/cellular level with cognitive impairment at the behavioral level. Our preliminary data shows that multiple genes involved with synaptic function and learning and memory are significantly altered in cortical neuron cultures treated with specific cytokine combinations. Additionally, direct infusion of these cytokine pools into the hippocampi of rats caused behavioral performance deficits in the spatial water maze task. From our preliminary findings, and the work of others, we propose the general hypothesis: Distinct cytokine pools differentially influence expression of genes associated with synaptic function and neurotransmission. These perturbations, and more specifically those altering the balance of glutamatergic signaling, modify neuronal circuit dynamics in the hippocampus during information processing, which results in cognitive impairment. Within the framework of our hypothesis we propose specific aims to address the following questions of how distinct cytokine pools differentially impact: (1) performance in distinct stages of learning and memory, (2) hippocampal neural circuit activity across stages of learning and memory, and (3) hippocampal RNA expression profiles, and expression and localization of specific synaptic proteins. Of particular importance is that the proposed experiments would represent the first systematic approach towards linking the impact of cytokines on cognition across behavioral, neural circuit, and molecular/cellular levels. Within the current literature, there are many studies that address the question of how cytokines impact behavior or how cytokines impact neural function, but none that encompass all three levels. As the middle ground needed to integrate molecular/cellular mechanisms with behavioral output, it is critical to understand how cytokines alter network properties of hippocampal circuits. At present, this level of analysis is generally absent from the literature. By integrating data generated from behavioral, neural circuit, and molecular/cellular levels from within single experiments, the Specific Aims of our proposal will lead to the development of a comprehensive top-down view of a how cytokines alter neuronal functions, which in turn impact brain function. PUBLIC HEALTH RELEVANCE: Cytokines are produced in the brain in response to a number of insults, including viral and bacterial infection, ischemia, psychological stress, and other brain traumas. Moreover, it is known that cytokines can adversely affect cognitive process, such as learning and memory. The proposed experiments will systematically examine the impact of brain cytokines on learning and memory, the activity of brain neuronal networks, and on changes in neuronal gene expression. Information obtained from these studies may prove useful for treatments to improve memory functions following neural trauma and injury, as well as in chronic diseases such as Alzheimer's Disease.